Differentiation induction in acute promyelocytic leukemia

Hematopoiesis or blood cell formation is a continuous process in which maturing hematopoietic cells with a limited life span are formed. The formation of all different blood cell lineages originates from a small population of pluripotent stem cells that reside in the bone marrow. Progenitor cells that are committed to a certain lineage of differentiation orginate from these pluripotent stem cells. Hematopoiesis is regulated by a network of cytokines and hematopoietic growth factors (HGF). The HGFs are produced locally by stromal cells. mature blood cells, endothelial cells or specialized cells in organs such as lungs, liver and kidney. The levels of HGFs are elevated in response to extracellular stimuli, such as infection or bleeding, when a rapid rise of specific blood cell types is necessary. HGFs exert their effect by binding to their corresponding receptors expressed on the membrane of their target cells. Ligand binding results in the activation of downstream signaling pathways. A cascade of phosphorylation events is involved in signal transduction. In one pathway, the JAK Uanus kinase) family of protein tyrosine kinases are tyrosine phosphorylated and in turn activate a family of latent cytoplasmic transcription factors, called STAT (Signal Transduction and Activation of Transcription) proteins. Following their activation, these STAT proteins are assembled into complexes which then translocate to the nucleus and activate target genes by interaction with specific DNA sequences. Another major HGF receptor signal transduction pathway includes proteins that belong to the Ras family. Signaling molecules like Shc and Grb2 function as adaptor proteins in this pathway by linking phosphorylated receptors to downstream effectors. Grb2 binds to the activated receptor, and to Sos (Son of sevenless) which after translocation to the plasma membrane activates Ras triggering phosphorylation of Rat. The products of Raf, a serine tyrosine kinase and mitogen activated protein kinases (MAPK) transmit signals for futher transmission to the nucleus. In the nucleus, activation of transcription factors by phosphorylation or other mechanisms results in activation of genes involved in cellular proliferation and differentiation. Apart from affecting transcription, activated Ras results in cyclin D1 activation and stimulates p27kip1 degradation via Rho. Both events positively infiuence cell cycle entry (Figure 1.2)

Drug Utilisation Patterns of Alternatives to Ranitidine-Containing Medicines in Patients Treated with Ranitidine:A Network Analysis of Data from Six European National Databases

Introduction: Ranitidine, a histamine H2-receptor antagonist (H2RA), is indicated in the management of gastric acid-related disorders. In 2020, the European Medicines Agency (EMA) recommended suspension of all ranitidine-containing medicines in the European Union (EU) due to the presence of N-nitrosodimethylamine (NDMA) impurities, which were considered to be carcinogenic. The aim of this study was to investigate the impact of regulatory intervention on use patterns of ranitidine-containing medicines and their therapeutic alternatives. Objectives: The aim was to study drug utilisation patterns of ranitidine and report discernible trends in treatment discontinuation and switching to alternative medications. Methods: This retrospective, population-based cohort study was conducted using primary care records from six European countries between 2017 and 2023. To explore drug utilisation patterns, we calculated (1) incident use of ranitidine, other H2RAs, and other alternative drugs for the treatment of gastric ulcer and/or gastric bleeding; (2) ranitidine discontinuation; and (3) switching from ranitidine to alternative drugs (H2RAs, proton-pump inhibitors [PPIs], and other medicinal products for acid-related disorders). Results: During the study period, 385,273 new ranitidine users were observed, with most users being female and aged 18–74 years. Ranitidine was the most commonly prescribed H2RA in the pre-referral period (September 2017–August 2019), with incidence rates between 0.8 and 9.0/1000 person years (PY). A steep decline to 0.3–3.8/1000 PY was observed in the referral period (September 2019–March 2020), eventually dropping to 0.0–0.4/1000 PY in the post-referral period (April 2020–March 2022). Switching from ranitidine to alternative drugs increased in the post-referral period, with the majority of patients switching to PPIs. Discontinuation of ranitidine use ranged from 270 to 380/1000 users in 2017 and decreased over time. Conclusions:Ranitidine was commonly used prior to referral, but it was subsequently discontinued and replaced primarily with PPIs.</p

Giochi da senatori

Megalencephalic leucoencephalopathy with subcortical cysts is a genetic brain disorder with onset in early childhood. Affected infants develop macrocephaly within the first year of life, after several years followed by slowly progressive, incapacitating cerebellar ataxia and spasticity. From early on, magnetic resonance imaging shows diffuse signal abnormality and swelling of the cerebral white matter, with evidence of highly increased white matter water content. In most patients, the disease is caused by mutations in the gene MLC1, which encodes a plasma membrane protein almost exclusively expressed in brain and at lower levels in leucocytes. Within the brain, MLC1 is mainly located in astrocyte-astrocyte junctions adjacent to the blood-brain and cereborspinal fluid-brain barriers. Thus far, the function of MLC1 has remained unknown. We tested the hypothesis that MLC1 mutations cause a defect in ion currents involved in water and ion homeostasis, resulting in cerebral white matter oedema. Using whole-cell patch clamp studies we demonstrated an association between MLC1 expression and anion channel activity in different cell types, most importantly astrocytes. The currents were absent in chloride-free medium and in cells with disease-causing MLC1 mutations. MLC1-dependent currents were greatly enhanced by hypotonic pretreatment causing cell swelling, while ion channel blockers, including Tamoxifen, abolished the currents. Down regulation of endogenous MLC1 expression in astrocytes by small interfering RNA greatly reduced the activity of this channel, which was rescued by overexpression of normal MLC1. The current-voltage relationship and the pharmacological profiles of the currents indicated that the channel activated by MLC1 expression is a volume-regulated anion channel. Such channels are involved in regulatory volume decrease. We showed that regulatory volume decrease was hampered in lymphoblasts from patients with megalencephalic leucoencephalopathy. A similar trend was observed in astrocytes with decreased MLC1 expression; this effect was rescued by overexpression of normal MLC1. In the present study, we show that absence or mutations of the MLC1 protein negatively impact both volume-regulated anion channel activity and regulatory volume decrease, indicating that megalencephalic leucoencephalopathy is caused by a disturbance of cell volume regulation mediated by chloride transport. © 2011 The Author

Reducing cardiometabolic risk in adults with a low socioeconomic position: protocol of the Supreme Nudge parallel cluster-randomised controlled supermarket trial

This erratum describes changes made in our previously published study protocol [1], as the occurrence of the COVID-19 pandemic has led to insurmountable challenges in feasibility to maintain the original design. The planned start of participant recruitment for the trial coincided with the first COVID-19 lockdown in the Netherlands starting March 16 2020. As a result, the start of the study was postponed by 11 months. The continued/renewed lockdown hampered face-to-face contact and thus some planned physical measurements. These circumstances required adaptation to remote data collection methods, revision of recruitment goals and of the primary study outcomes, and inclusion of additional study sites to secure adequate participant inclusion rates. Therefore, below we present the revised methodology of the Supreme Nudge parallel cluster-randomised controlled supermarket trial. All changes made to the original protocol were reviewed and approved by the Medical Ethics Review Committee of VU University Medical Center (reference number: 2019.334) prior to implementation

Diagnostic yield and accuracy of CT angiography, MR angiography, and digital subtraction angiography for detection of macrovascular causes of intracerebral haemorrhage: Prospective, multicentre cohort study

Study question What are the diagnostic yield and accuracy of early computed tomography (CT) angiography followed by magnetic resonance imaging/angiography (MRI/MRA) and digital subtraction angiography (DSA) in patients with non-traumatic intracerebral haemorrhage? Methods This prospective diagnostic study enrolled 298 adults (18-70 years) treated in 22 hospitals in the Netherlands over six years. CT angiography was performed within seven days of haemorrhage. If the result was negative, MRI/MRA was performed four to eight weeks later. DSA was performed when the CT angiography or MRI/MRA results were inconclusive or negative. The main outcome was a macrovascular cause, including arteriovenous malformation, aneurysm, dural arteriovenous fistula, and cavernoma. Three blinded neuroradiologists independently evaluated the images for macrovascular causes of haemorrhage. The reference standard was the best available evidence from all findings during one year's follow-up. Study answer and limitations A macrovascular cause was identified in 69 patients (23%). 291 patients (98%) underwent CT angiography; 214 with a negative result underwent additional MRI/MRA and 97 with a negative result for both CT angiography and MRI/MRA underwent DSA. Early CT angiography detected 51 macrovascular causes (yield 17%, 95% confidence interval 13% to 22%). CT angiography with MRI/MRA identified two additional macrovascular causes (18%, 14% to 23%) and these modalities combined with DSA another 15 (23%, 18% to 28%). This last extensive strategy failed to detect a cavernoma, which was identified on MRI during follow-up (reference strategy). The positive predictive value of CT angiography was 72% (60% to 82%), of additional MRI/MRA was 35% (14% to 62%), and of additional DSA was 100% (75% to 100%). None of the patients experienced complications with CT angiography or MRI/MRA; 0.6% of patients who underwent DSA experienced p

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities 1,2 . This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity 3�6 . Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55 of the global rise in mean BMI from 1985 to 2017�and more than 80 in some low- and middle-income regions�was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing�and in some countries reversal�of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories. © 2019, The Author(s)

The principal mechanism underlying megalencephalic leukoencephalopathy with subcortical cysts, implications for white matter water homeostatis

promotiedatum: 8-3-201